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Abstract

Sugammadex is a revolutionary investigational reversal drug currently undergoing Phase III testing whose introduction into clinical practice may change the face of clinical neuromuscular pharmacology. A modified γ-cyclodextrin, sugammadex exerts its effect by forming very tight water-soluble complexes at a 1:1 ratio with steroidal neuromuscular blocking drugs (rocuronium > vecuronium ≫ pancuronium). During rocuronium-induced neuromuscular blockade, the IV administration of sugammadex creates a concentration gradient favoring the movement of rocuronium molecules from the neuromuscular junction back into the plasma, which results in a fast recovery of neuromuscular function. Sugammadex is biologically inactive, does not bind to plasma proteins, and appears to be safe and well tolerated. Additionally, it has no effect on acetylcholinesterase or any receptor system in the body. The compound's efficacy as an antagonist does not appear to rely on renal excretion of the cyclodextrin-relaxant complex. Human and animal studies have demonstrated that sugammadex can reverse very deep neuromuscular blockade induced by rocuronium without muscle weakness. Its future clinical use should decrease the incidence of postoperative muscle weakness, and thus contribute to increased patient safety. Sugammadex will also facilitate the use of rocuronium for rapid sequence induction of anesthesia by providing a faster onset-offset profile than that seen with 1.0 mg/kg succinylcholine. Furthermore, no additional anticholinesterase or anticholinergic drugs would be needed for antagonism of residual neuromuscular blockade, which would mean the end of the cardiovascular and other side effects of these compounds. The clinical use of sugammadex promises to eliminate many of the shortcomings in our current practice with regard to the antagonism of rocuronium and possibly other steroidal neuromuscular blockers.

Sugammadex is a novel and unique compound designed as an antagonist of rocuronium and possibly other steroidal neuromuscular blockers. This investigational drug is currently in Phase IIIa multicenter trial in the United States, and is likely to be introduced to the market in the future. In this article, I address the unique characteristics of sugammadex and offer a vision for how this drug is likely to change anesthesia practice.

HISTORICAL PERSPECTIVE

The cornerstone of modern neuromuscular pharmacology was laid more than seven decades ago when the chemical theory of the role of acetylcholine in neuromuscular transmission was established by Dale (1,2). The first successful administration of curare to produce surgical relaxation in an anesthetized patient had occurred in 1912, when Arthur Läwen, a German surgeon from Leipzig, used a partially purified preparation of the substance (3). Läwen's findings were subsequently ignored for nearly three decades until January 23, 1942, when Enid Johnson, following Harold Griffith's instructions, administered a total of 5 mL of curare IV to a 20-year-old man who had been anesthetized with cyclopropane via a facemask for an appendectomy. The anesthesia lasted for 70 min and was later described as being “nothing less than dramatic” (4). It was without a doubt, a revolutionary step and a milestone that changed anesthetic practice. However, when this technique was initially used, patients were not fully paralyzed, and the pharmacological antagonism of the residual neuromuscular blockade of curare was hardly considered (5). Tracheal intubation and controlled ventilation were also uncommon in routine clinical practice.

The clinical use of neuromuscular blockers in anesthesia has come a long way since then. Since the 1980s, we have witnessed the introduction of many new nondepolarizing neuromuscular blocking drugs into clinical practice. In that decade, the two major pharmaceutical competitors (Organon and Burroughs Wellcome) were focused on developing nondepolarizing neuromuscular blockers that would fit the criteria of an “ideal” nondepolarizing blocker (6). Many modern neuromuscular blocking drugs, such as vecuronium, rocuronium, and cisatracurium, were introduced into clinical practice at that time. These new drugs had significant clinical advantages and minimized the side effects associated with older compounds such as d-tubocurarine and pancuronium.

Given these strides in anesthetic pharmacology, do any problems remain? Unfortunately, neuromuscular blocking drugs are among the most poorly used drugs in our armamentarium. Reports of residual postoperative weakness, incomplete recovery (7–9), and undesired ventilatory effects (10,11) have continued to appear since 1979. In 2003, for example, Debaene et al. (9) reported a 45% incidence of postoperative residual paralysis in patients arriving in the postanesthesia care unit. A recent survey has indicated that most practitioners do not know what constitutes adequate recovery from neuromuscular blockade (12). The aforementioned problems could be attributed to two main factors. First, most anesthesiologists do not routinely use quantitative neuromuscular function monitors to ensure adequate recovery to a train-of-four (TOF) ratio of 0.9 or more (13,14). Although anesthesiologists are fast to adopt new monitoring technologies, such as capnography, pulse oximetry, and bispectral index monitoring, the same is not true for neuromuscular function monitoring; the reasons for the limited use of such monitoring are unknown. Second, neostigmine has a ceiling effect and, when administered at a deep level of neuromuscular blockade, can result in an inadequate recovery of neuromuscular function (15,16).

So, what is still needed? It is clear that no substantial progress has been made in the area of neuromuscular antagonism. In 2006, neostigmine is still the most common anticholinesterase drug used by anesthesiologists worldwide, despite its undesirable side effects (17). Few studies have attempted to explore the potential of nonclassic reversal drugs. In this regard, suramin, a P2-purinoceptor antagonist, can reverse nondepolarizing neuromuscular blockade (18–20), but it has serious side effects that render it inapplicable for routine clinical use (21). In contrast, purified human plasma cholinesterase has been shown to be an effective and safe drug in antagonizing mivacurium-induced neuromuscular blockade (22–24). Similarly, cysteine has been shown to reverse the neuromuscular blocking effects of gantacurium (25). Notably, both purified human plasma cholinesterase and cysteine act independently of acetylcholinesterase inhibition.

CHEMISTRY OF SUGAMMADEX

Phase IIIa studies are currently underway in the United States and Europe testing a member of a new class of reversal drugs. This drug, sugammadex (ORG 25969), is a modified γ-cyclodextrin (26–29). (Su refers to sugar and gammadex refers to the structural molecule γ-cyclodextrin). The three natural unmodified cyclodextrins consist of 6, 7, or 8 cyclic oligosaccharides (i.e., dextrose units joined through 1–4 glycosyl bonds) and are called α-, β-, or γ-cyclodextrin, respectively. Their three-dimensional structures resemble a hollow, truncated cone or a doughnut. The structure has a hydrophobic cavity and a hydrophilic exterior because of the presence of polar hydroxyl groups. Hydrophobic interactions trap the drug into the cyclodextrin cavity (the doughnut hole), resulting in the formation of a water-soluble guest–host complex. For this reason, cyclodextrins have been used as solubilizing agents for many United States Food and Drug Administration-approved drugs (30–32), and have been evaluated as solvents for different anesthetic drugs such as propofol (33,34), midazolam (35), bupivacaine (36), and sufentanil (37).

Although unmodified γ-cyclodextrin has a larger lipophilic cavity than any other cyclodextrin, it is still not deep enough to accommodate the larger rigid structure of the rocuronium molecule. Therefore, the drug was modified by adding eight side chains to extend the cavity to better accommodate the four hydrophobic steroidal rings of rocuronium, and by adding negatively charged carboxyl groups at the end of the side chains to enhance electrostatic binding to the positively charged quaternary nitrogen of rocuronium (Figs. 1 and 2) (26,27). These modifications resulted in a sugammadex compound that is highly water soluble with a hydrophobic cavity large enough to encapsulate steroidal neuromuscular blocking drugs, especially rocuronium (26–29). The stability of the rocuronium–sugammadex complex is the end result of interplay of intermolecular (van der Waals) forces, including thermodynamic (hydrogen bonds) and hydrophobic interactions (34). The molecular weight of sugammadex sodium salt is 2178.01. Sugammadex is, therefore, the first selective relaxant binding agent (SRBA).

MECHANISM OF ACTION OF SUGAMMADEX

Sugammadex exerts its effect by forming very tight complexes at a 1:1 ratio with steroidal neuromuscular blocking drugs (rocuronium > vecuronium ≫ pancuronium) (Fig. 3) (26–29). The guest–host complex exists in equilibrium with a very high association rate (an association constant of 107 M−1) and a very low dissociation rate, so the complex is tight (26).

During rocuronium-induced neuromuscular blockade, the IV administration of sugammadex results in rapid removal of free rocuronium molecules from the plasma. This creates a concentration gradient favoring the movement of the remaining rocuronium molecules from the neuromuscular junction back into the plasma, where they are encapsulated by free sugammadex molecules (38–40). The latter molecules also enter the tissues and form a complex with rocuronium. Therefore, the neuromuscular blockade of rocuronium is terminated rapidly by the diffusion of rocuronium away from the neuromuscular junction back into the plasma (38–44). This results in an increase in the total plasma concentration of rocuronium (both free and bound to sugammadex) (38). Because of the low dissociation rate, no muscle weakness has been reported in available human or animal studies (38–44). Sugammadex, therefore, acts as a binding drug and has no effect on acetylcholinesterase or any receptor system in the body. This eliminates the need for anticholinergic drugs, thus avoiding their undesirable side effects. The findings of sugammadex's reversal of rocuronium-induced neuromuscular blockade have theoretical implications as well (38–44). They disprove the historical hypothesis of Feldman and Tyrrell (45) that reducing the plasma concentration of nondepolarizing neuromuscular blockers does not reverse the neuromuscular blockade.

The compound's efficacy as an antagonist does not appear to rely on renal excretion of the cyclodextrin-relaxant complex (46). Most sugammadex is excreted unchanged in the urine in the first 8 h (40). Sugammadex also increases the amount of rocuronium excreted unchanged in the urine (40), but a change in acid–base status affects anticholinesterase activity, it appears not to influence the efficacy of sugammadex1.

EFFECT OF SUGAMMADEX ON OTHER DRUGS

Sugammadex is ineffective against succinylcholine and benzylisoquinolinium neuromuscular blockers, such as mivacurium, atracurium, and cisatracurium (44), because it cannot form inclusion complexes with these drugs. Therefore, if neuromuscular blockade must be re-established after using sugammadex, succinylcholine or one of the benzylisoquinolinium neuromuscular blockers should be considered. Under these conditions, what would be the potency of cisatracurium and succinylcholine? Sugammadex binds at a 1:1 ratio to rocuronium and vecuronium, but for effective reversal, all rocuronium or vecuronium molecules do not have to be complexed with sugammadex. The margin of safety of the neuromuscular transmission is such that only 20%–25% of postsynaptic receptors need to be free for transmission to occur (47). Therefore, sugammadex only has to reduce the occupation of these receptors from 100% to 70% to obtain complete reversal. After induction of neuromuscular blockade with rocuronium and complete reversal with sugammadex in anesthetized guinea pigs, the administration of cisatracurium caused a more intense neuromuscular blockade with a faster than normal onset (48). Kopman et al. (49) also demonstrated that the ED50 of mivacurium was 56% less if calculated after full recovery from mivacurium-induced neuromuscular blockade than after the initial blockade. When succinylcholine rather than cisatracurium was administered, complete blockade could also be induced; however, its onset was delayed in the guinea pig (48). Pretreatment with nondepolarizing neuromuscular blockers had a marked antagonistic effect on the development of the subsequent depolarizing blockade produced by succinylcholine (50).

The interaction of sugammadex with other molecules has been tested with isothermal titration microcalorimetry. This technique measures the heat production when two molecules form a complex. The ability of sugammadex to form complexes with other steroidal and nonsteroidal compounds, such as cortisone, atropine, and verapamil, is probably clinically insignificant and is approximately 120–700 times less than that of rocuronium (51). Steroidal molecules form complexes with sugammadex, but with a much lower affinity, because the high affinity of sugammadex for rocuronium and vecuronium is caused by the interaction between the negatively charged carboxyethyl side chains of sugammadex and the positively charged quaternary nitrogen of rocuronium and vecuronium. As endogenous steroidal hormones and steroidal drugs lack the quaternary nitrogen of the steroidal blockers, they show a much lower affinity. Furthermore, steroidal hormones are also bound tightly to specific protein carriers; for example, the sex hormones are bound with very high affinity to globulin.

The possible effects of the sugammadex-induced improved solubility of propofol, midazolam, and bupivacaine on the pharmacodynamics/pharmacokinetics of these compounds have not yet been studied.

ANIMAL STUDIES

All animal studies have thus far demonstrated that sugammadex is effective in antagonizing rocuronium-induced neuromuscular blockade without any significant effects on arterial blood pressure or heart rate (39,42–44). In one study that used anesthetized guinea pigs, rocuronium was infused for 1 h to maintain a steady state 90% neuromuscular blockade (39). After 30 min, a concomitant infusion of sugammadex at a rate of 50 nmol · kg−1 · min−1 resulted in rapid reversal of the neuromuscular blockade. An average twitch recovery of approximately 80%, 90%, and 100% occurred 10, 20, and 30 min, respectively, after the start of the sugammadex infusion (39). This was accompanied by an increase in the total plasma concentration of rocuronium (free and that encapsulated by sugammadex). In contrast, the plasma concentration of rocuronium and the depth of neuromuscular blockade remained unchanged in saline-treated animals. In clinical practice, the antagonism of residual neuromuscular blockade is normally attempted after discontinuing infusion of neuromuscular blockers. The ability of sugammadex to antagonize the neuromuscular blockade despite concomitant infusion of rocuronium points out its unique characteristics. The study design also explains the prolonged recovery times noted (39).

VOLUNTEERS AND CLINICAL STUDIES

The effectiveness of sugammadex is dose dependent. In male volunteers, the administration of 8 mg/kg sugammadex 3 min after the administration of 0.6 mg/kg rocuronium resulted in the recovery of the TOF ratio to 0.9 within 2 min (38). Decreasing the dose of sugammadex to 4 mg/kg resulted in a recovery of the TOF ratio to 0.9 in <4 min (38). In one study, different doses of sugammadex or placebo were administered to surgical patients anesthetized with total IV anesthesia who had received 0.6 mg/kg rocuronium at the reappearance of the second twitch of the TOF response (40). Sugammadex decreased the median recovery time in a dose-dependent manner from 21.0 min in the placebo group to 1.1 min in the group receiving 4.0 mg/kg sugammadex. The authors of this study concluded that doses of 2.0–4.0 mg/kg of sugammadex reversed rocuronium-induced neuromuscular blockade within 3 min (40). In another study, deep neuromuscular blockade (posttetanic count of <10) was maintained for at least 2 h in patients anesthetized with propofol–nitrous oxide– opioid anesthesia (41). After the spontaneous recovery of the second twitch of the TOF, different doses of sugammadex were administered; increasing the sugammadex dose from 0.5 to 4.0 mg/kg shortened the average recovery time to a TOF of 0.9 from 6.8 min (range, 4.8–11.4 min) to 1.4 min (range 0.95–2.3 min), respectively (41). Unexpectedly, the recovery time was longer (2.6 min [range 1.3–3.9 min]) with a 6.0 mg/kg dose (41). The reason for this deviation is unclear, but the reversal still occurred in <3 min, on average.

Currently, as a part of a multicenter study, we are comparing the speed of recovery from 1.2 mg/kg rocuronium followed 3 min later by 16 mg/kg sugammadex with that of spontaneous recovery from 1.0 mg/kg succinylcholine in surgical patients. Our initial results are very encouraging with respect to the antagonism of this profound level of rocuronium-induced neuromuscular blockade and indicate that the total duration from administration of rocuronium until a TOF ratio recovery to more than 0.9 is shorter than the time needed for spontaneous recovery from 1.0 mg/kg succinylcholine-induced blockade to a similar degree of recovery (Fig. 4).

SIDE EFFECTS

Sugammadex is biologically inactive, does not bind to plasma proteins, and appears to be safe and well tolerated (38,40,50). The safety of sugammadex has been assessed in the phase I and II studies (in a total of 86 subjects). In one study, sugammadex was administered to awake volunteers who had received no neuromuscular blocking drugs (38). The most frequently reported side effects have been hypotension (three subjects), coughing (three subjects), movement (three subjects), nausea (three subjects), vomiting (three subjects), dry mouth (four subjects), parosmia (an abnormal smell) (two subjects), a sensation of a changed temperature (three subjects), and abnormal levels of N-acetyl-glucosaminidase in the urine (five subjects) (38,40,41). In one study, prolongation of the corrected QT interval was noted in five subjects who received placebo and in three subjects who received sugammadex (38).

FUTURE APPLICATIONS AND CHALLENGES

What can we look forward to? Does the introduction of sugammadex herald the elimination of many of the shortcomings in our clinical practice with regard to antagonism of neuromuscular blockers? The deep levels of neuromuscular blockade induced by rocuronium (and possibly by vecuronium, although there is no clinical evidence for the latter drug yet) can be promptly antagonized with appropriate doses of sugammadex. This should make surgical care much easier and safer: Surgeons should no longer encounter inadequate muscle relaxation, and anesthesiologists should no more encounter patients whose neuromuscular blockade is hard to reverse at the end of surgery. The introduction of sugammadex into clinical practice would thus contribute to both increased patient safety and improved surgical conditions. One expects to see no more patients either being held in the operating room because the antagonism of residual neuromuscular blockade is incomplete, or being transferred to postoperative care units with residual neuromuscular blockade. Additionally, no anticholinesterase or anticholinergic drugs would be needed for the antagonism of residual neuromuscular blockade, which would mean the end of the cardiovascular and other side effects of these compounds (17). The postoperative nausea and vomiting associated with the use of these compounds should also be eliminated (52). Will sugammadex replace neostigmine as an antagonist for rocuronium-induced neuromuscular blockade? Kopman (53) rightly believes that this will “… depend at least in part on economic considerations.” Although concerns have been raised about the acquisition cost of new drugs (54), the economic evaluations are complex, and not simply defined by the acquisition cost (55). In the final analysis, improvements in inpatient outcome must have a dollar value that offsets the cost of the drug (56).

Do we still need to use neuromuscular function monitoring with sugammadex? Without knowing the depth of the rocuronium-induced neuromuscular blockade, it would be difficult to know the dose of sugammadex needed. Perhaps conventional nerve stimulators would be sufficient to determine the presence or absence of the twitch response, and the appropriate dose of sugammadex could be administered accordingly. In such circumstances, objective neuromuscular monitoring would no longer be needed.

Further, the use of rapid-sequence induction with rocuronium can be facilitated by the presence of sugammadex. The previously described sequence of 1.2 mg/kg rocuronium followed 3 min later by 16 mg/kg sugammadex seems to provide a faster onset-offset profile than that seen with 1.0 mg/kg succinylcholine. If the rocuronium induction/sugammadex reversal paradigm achieves the reliability of succinylcholine, will this mark the end of years of effort directed toward developing a nondepolarizing version of succinylcholine? Why would one ever give succinylcholine if one could give rocuronium and achieve reversal more quickly than the succinylcholine would wear off? Before these questions can be answered, however, we must know whether the rocuronium-sugammadex sequence will be safer than succinylcholine? In this regard, studies using succinylcholine have indicated that the risk of desaturation in the immediate postinduction period is much greater than initially recognized in “cannot intubate, cannot ventilate” situations (57,58). Nevertheless, studies are needed to address the role of sugammadex as a “rescue” reversal drug in patients with unanticipated difficult airways who received rocuronium. For now, succinylcholine is expected to remain on the hospital formulary, but its clinical use will most likely become limited to reparalyzing patients who have already received sugammadex.

The introduction of propofol almost two decades ago changed anesthetic practice (34). Nothing since then, however, has had the same effect. Unquestionably, the introduction of sugammadex is an important breakthrough, and one that is likely to change the face of clinical neuromuscular pharmacology. This molecule is specifically suited to rocuronium and vecuronium, and its future clinical use should decrease the incidence of postoperative muscle weakness caused by these drugs and facilitate the use of rocuronium for rapid sequence induction of anesthesia. For now, however, we still need benzylisoquinolinium neuromuscular blockers in our practice, so the residual postoperative muscle weakness caused by this class of drugs is likely to continue unless objective neuromuscular function monitors are routinely used, or until a molecule capable of binding to benzylisoquinolinium neuromuscular blockers is discovered.

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